Bioabsorbable Co-Filler for Cerebrovascular Aneurysms

ABSTRACT

Materials and Methods for delivering materials for filling aneurysms in which the materials comprise a glycosaminoglycan and optionally, contrast media and physiological buffers and in which delivery methods include percutaneous delivery with a balloon catheter or a needle catheter.

BACKGROUND

In many cases, aneurysms form in the vessel walls of an organism. Ifsuch an aneurysm were to rupture, the organism would be in danger ofseverely bleeding from the rupture site. Depending on the location ofthe aneurysm, its rupture could lead to stroke. And if large enough, theaneurysm's rupture could even lead to exsanguination.

The extreme risks associated with aneurysms call for their treatment.Typical treatments of un-ruptured aneurysms include surgically removingthem in situations where such removal is possible. Another treatmentcenters on filling an aneurysm sack with coils of various materials,which may decrease the pressure in the sack. In some cases, the dangerfrom the aneurysm decreases when the pressure in the sack falls. Toreduce the pressure in the sack, it is important to fill the sack well,and then slowly allow the sack to fill up with scarring or otherextracellular matrix material. A practitioner could orchestrate slowfilling followed by scarring or the migration of other matrix materialusing coils with bioabsorbable, pro-inflammatory coatings.Alternatively, changes in the hemodynamics cause by filling the aneurysmpromote the formation of thrombus inside the aneurysm sack, which alsolowers aneurysm pressure.

In many cases, filling treatment results in an aneurysm permanentlyfilled with foreign material. This treatment may lower the pressure andrestore normal hemodynamics near the aneurysm. But it also interfereswith the aneurysm's complete healing.

What is needed is a way to temporarily fill the aneurysm in acontrollable manner such that endogenous compounds could later graduallyreplace the filling material.

SUMMARY

As in one inventive embodiment, one useful filling material is acomposition that comprises a glycosaminoglycan or a mucopolysaccharide.In some embodiments, this composition is augmented with a physiologicalbuffer, with a contrast media or with both.

Additionally, some embodiments are formed in-situ, inside of theaneurysm sack and may additionally comprise avian protein, blood proteincomponents, blood protein decomposition products, blood cells, bloodcell decomposition products, other endogenous compounds, or coildecomposition products.

In some embodiments, the filling material is prepared as a hydrogel.

In some embodiments, the filling material is prepared so that it slowlymigrates out of the aneurysm or is broken down within the aneurysm andreplaced by endogenous compounds over a 7-90 day period; 14-70 dayperiod; or 21-60 day period.

Some embodiments are directed at methods for treating aneurysms. Forexample, in one embodiment the method of treating an aneurysm comprisesdelivering a glycosaminoglycan or a mucopolysaccharide to the aneurysmor into an aneurysm. Moreover, various embodiments in which an aneurysmis treated by delivering a filling material as described in thisdocument, to the aneurysm or into the aneurysm. A variation of theseembodiments includes delivering a metallic or polymeric coil to theaneurysm before, during, or after delivery of the filling material ordelivery of a glycosaminoglycan or a mucopolysaccharide.

Some embodiments use direct surgery or hypodermic needle deliverydirectly to the aneurysm. Other embodiments use balloon or needlecatheters to deliver the filling material to the aneurysmpercutaneously.

DETAILED DESCRIPTION

The following description of several embodiments describes non-limitingexamples that further illustrate the invention. All titles of sectionscontained herein, including those appearing above, are not to beconstrued as limitations on the invention, but rather they are providedto structure the illustrative description of the invention that isprovided by the specification.

Unless defined otherwise, all technical and scientific terms used inthis document mean what one skilled in the art to which the disclosedinvention pertains commonly understands them to mean. Singular forms—a,an, and the—include plural referents unless the context clearlyindicates otherwise. Thus, for example, reference to “fluid” refers toone or more fluids, such as two or more fluids, three or more fluids,etc. When an aspect is said to include a list of components, the list isrepresentative. If the component choice is specifically limited to thelist, the disclosure will say so. Moreover, listing componentsacknowledges that embodiments exist for each of the components and anycombination of the components—including combinations that specificallyexclude any one or any combination of the listed components. Forexample, “component A is chosen from A, B, or C” discloses embodimentswith A, B, C, AB, AC, BC, and ABC. It also discloses (AB but not C), (ACbut not B), and (BC but not A) as embodiments, for example. Combinationsthat one of ordinary skill in the art knows to be incompatible with eachother or with the components' function in the invention are excludedfrom the invention, in some embodiments.

In some embodiments, treatment methods include delivering a material tothe aneurysm. So that the physician can monitor the degree of filling ofthe aneurysm, the material mixture may contain a contrast medium, which,for example fluoroscopy, could reveal during the treatment. The exactmechanics of delivering a material to the aneurysm depends on which typeof aneurysm afflicts the patient.

Some aneurysms consist of larger regions of weakened vessel wall thatmay bulge from the normal vessel walls, pushed out by the blood pressurewithin the vessel. Other aneurysms consist of a weakening of a smallerregion of the vessel wall that then balloons out from the vessel wallagain pushed out by blood pressure within the vessel. These aneurysmtypes serve as the ends of a continuum that encompasses most aneurysms.

A difference between these two types of aneurysms is in their ability tocontain a treatment agent. For example, an aneurysm with more of aballoon-like structure may be able to accept and hold a material thatblood flow would wash away from a less balloon-like aneurysm or ananeurysm that simply bulges from a larger region of vessel wall. Thus,sometimes a practitioner treats aneurysm with a coil of polymeric ormetallic wire such as a coil of platinum wire before introducing a“filling” material. In some embodiments, treatment comprises deliveringthe material to the aneurysm before, after, or during the delivery ofthe coil.

Regardless of the type of aneurysm and regardless of whether using acoil promotes retaining a filling material at the aneurysm site,practitioners may choose to treat the aneurysm with a filling materialand either use or omit a coil at their discretion. All instances oftreating an aneurysm with the filling material described in thisdocument (with or without a coil) are within the scope of the invention.

In some embodiments, the filling material comprises a glycosaminoglycanor a mucopolysaccharide. One advantage of using a glycosaminoglycan or amucopolysaccharide is that, over time, these materials can be replacedby compounds that are endogenous to the body. Thus, over time, thefilling material disappears along with the contrast medium. As one ofordinary skill in the art will recognize, examination of the treatmentsite days to months after treatment will reveal less and less of animage as endogenous compounds replace the filing material (and thecontrast medium). By analyzing the intensity changes at the treatmentsite, a physician can monitor the degree of healing of the aneurysm.

Another advantage of using glycosaminoglycans or mucopolysaccharides isthat these large molecules show extremely little variation species tospecies. Therefore, human glycosaminoglycans are almost identical toavian glycosaminoglycans allowing the use of the avian glycosaminoglycanor mucopolysaccharide in treating a human patient without substantialrisk of a foreign body reaction in the human patient. In fact, mostmedical grade glycosaminoglycans or mucopolysaccharides are producedfrom sources other than human sources and may contain residual proteinsor other materials from those sources.

Once the aneurysm is filled, the hydrodynamics of the blood near theaneurysm become less abnormal. Subsequently, the filling material beginsto break down and thrombin, blood cell decomposition products, bloodprotein components, other endogenous materials, and, in the case ofaneurysms also treated with a coil, the decomposition products of thecoil or any coil coating all begin to take the place of the fillingmaterial. For purposes of this disclosure, coil decomposition productsare materials that were once part of a medical device that was insertedinto an aneurysm. In some cases, the device was a wire coil, hence theterm coil decomposition products. Coil composition products need notcome from wire coils, but are the decomposition products from anymedical device, as discussed above.

For purposes of this disclosure, an aneurytic site is a region inmammalian vasculature near an aneurysm or near aneurytic tissue. And forpurposes of this disclosure, aneurytic tissue is any type of tissueassociated with or created by the formation of an aneurysm or any tissuecomposing an aneurysm or the vascular tissue near an aneurysm.

Filling Material

Various compositions are suitable for applying or supplying to or intoan aneurysm to treat it. The filling material of the current inventioncomprises a base (Component I) and optionally a contrast agent or medium(Component II) and optionally a drug or bioactive agent (component III).Of course, other materials and formulations for use on mammalianpatients may also compose the filling material. One such material is aphysiological buffer.

In some embodiments, an invention composition comprises a mixture of theComponent I and Component II compositions. For purposes of thisdisclosure, an invention mixture is a combination of two or morecomponents in which the components substantially retain their chemicalidentity upon combination. The components substantially retain thechemical nature that they had before combination into the mixture.

Component I

In some embodiments, the base comprises a glycosaminoglycan or amucopolysaccharide. Useful glycosaminoglycans or mucopolysaccharidesinclude hyaluronic acid, sodium hyaluronate, chondroitin sulfate,dermatan sulfate, keratan sulfate, or heparin sulfate, in someembodiments. Also, useful polyanionic polysaccharides includecarboxymethylcellulose, carboxymethylamylose and their derivatives.These are described more fully below. In some embodiments, the basecomprises hyaluronic acid. In these or other embodiments, hyaluronicacid comprises HEALON (a product of Abbott Medical Optics). A variety ofembodiments use such HEALON bases, which are described below in thediscussion of U.S. Pat. Nos. 5,681,825; 6,086,597; and 6,271,216.

U.S. Pat. No. 5,681,825, issued October 1997, discloses examples ofuseful hyaluronic acid base materials. In some embodiments, the base isan aqueous solution of hyaluronic acid with an average molecular weightof 4 million to 12 million. In some of these embodiments, the zero shearviscosity of the base hyaluronic acid ranges from 1 thousand to 80thousand Pas. Other embodiments include hyaluronic acid bases with anaverage molecular weight of 4.5 million to 8 million. In some of theseembodiments, the zero shear viscosity of the material is 1 thousand to 9thousand Pas.

U.S. Pat. No. 6,086,597, issued in July 2000, also discloses examples ofuseful hyaluronic acid base materials. In some embodiments, the base isan aqueous solution of 18-40 mg sodium hyaluronate per milliliter ofwater in which the sodium hyaluronate has a <M>_(r,M)=1×10⁶ to 10×10⁶.In some embodiments, the base is an aqueous solution of 20 mg of<M>_(r,M)=3×10⁶ sodium hyaluronate; 8.5 milligrams of sodium chloride,and one milliliter of water. In some embodiments, the base is an aqueoussolution of 25 mg of <M>_(r,M)=3×10⁶ sodium hyaluronate; 8.5 milligramsof sodium chloride, and one milliliter of water.

U.S. Pat. No. 6,271,216, issued in August 2001, also discloses examplesof useful hyaluronic acid base materials. In some embodiments, the baseis an aqueous solution of about 0.1 to five percent by weight or one tothree percent by weight sodium hyaluronate having an average molecularweight of 0.2×10⁶ to 10.0×10⁶ or 0.25×10⁶ to 4×10⁶. These solutions havesodium ions present from about 80 to 185 millimolar or 90 to 110millimolar exclusive of the sodium contributed by the sodiumhyaluronate. In some embodiments, the solution is prepared with 30milligrams of sodium hyaluronate; 3-3.4 milligrams sodium chloride; andone milliliter of water. In some embodiments, the solution is preparedwith 30 milligrams sodium hyaluronate, 4.3-4.7 milligrams sodiumchloride, and one milliliter of water. In some embodiments, solutionsprepared with 30 milligrams sodium hyaluronate, 3.2 milligrams sodiumchloride, and one milliliter of water are useful. In some of theseembodiments, the sodium hyaluronate has an average molecular weight of400 thousand. Finally, as disclosed in the '216 patent, solutionsprepared with 30 milligrams of sodium hyaluronate with a molecularweight of 400 thousand; 4.58 milligrams of sodium chloride, and onemilliliter of water are useful in some embodiments as part of ComponentI. Some embodiments employ cross-linked hyaluronic acid as part of thebase, as well. One type of cross-linked hyaluronic acid has disulfidecross-links.

In addition to polyanionic polysaccharides and hyaluronic-acid-basedpolymers, modified polymers may be used in the present invention. Theseare disclosed in U.S. Pat. No. 7,829,118. Such polymers includepolyanionic polysaccharides that have been modified in a number of ways.In some embodiments, the unmodified polyanionic polysaccharides are anyone or any combination of hyaluronic acid, carboxymethylcellulose,carboxymethylamylose, chondroitin-4-sulfate, chondroitin-6-sulfate,dermatan sulfate, dermatin-6-sulfate, heparin sulfate, heparin, keratinsulfate and their derivatives.

Similar other useful polymers are known in the art, and described, forexample, in U.S. Pat. No. 6,056,970. Other biodegradable polymersinclude fibrin, fibrinogen, starch, poly(amino acids); peptides,proteins, gelatin and collagen.

Hyaluronic acid may be derivatized by reacting its hydroxyl groups withdivinyl sulfone. The hyaluronic acid will typically have a degree ofmodification of reactive hydroxyl groups ranging from 1 to 80%; 1 to50%; or 1 to 25%. That is to say, a 1% degree of modification orsubstitution means that an average of 1% of the hyaluronic aciddisaccharide units contain a vinyl sulfone group.

Alternatively, the polymer may be thiol-derivatized, such as athiol-derivatized hyaluronic acid. Exemplary thiol-derivatizedhyaluronic acid polymers include those described in U.S. Pat. Nos.6,884,788; 6,620,927; 6,548,081, 6,537,979; 606,013,679; U.S. Pat. Nos.5,502,081; and 5,356,883, relevant portions of which related to suchthiol-derivatized polymers being incorporated herein by reference intheir entireties.

Additional examples of hyaluronic acid polymers includecysteine-derivatized hyaluronic acid, including those polymers disclosedin “Controlled Release from Glycosaminoglycan Drug Complexes” R. V.Sparer et al.

Some embodiments use a gel comprised of the reaction product of twocomponents. In those embodiments that employ such a filling materialbase, the gel's components must be chosen so that the material sets uprelatively quickly—less than 60, 45, 30, 15, 5, or 1 seconds. Withinthat time, the material should exceed 80, 85, 90, or 95% of its finalviscosity or modulus. For example, a gel based on silk elastin materialsmay be used as a component of the filling material.

Various embodiments use a Component I that has one or more of thefollowing features: a non-particulate nature; a flowable nature; or anon-fibrotic nature. For purposes of this disclosure, having anon-particulate nature means that neither the glycosaminoglycan nor themucopolysaccharide of Component I has been subjected to any physical orchemical treatment designed to make it take the form of a particle. Forpurposes of this disclosure, having a flowable nature means that theglycosaminoglycan or mucopolysaccharide of Component I can flow within adelivery device. For purposes of this disclosure, having a non-fibroticnature means that the glycosaminoglycan or mucopolysaccharide ofComponent I does not produce enough fibrotic tissue to produce apermanent or obstructive scar in the vasculature.

A non-thrombogenic material is any material that, when inserted intomammalian vasculature, does not have a tendency to produce a blood clotsubstantially higher than the tendency of vascular tissue to produce ablood clot, when measured over a 1-hour, 2-hour, 1-day, 2-day, 1-week,or 2-week time.

For purposes of this disclosure, a high viscosity material is a materialwith a viscosity greater than or equal to that of mammalian blood, witha viscosity sufficiently high to prevent substantial mixing between thematerial and blood for 1-1000; 2-100; 2-50; 2-25; or 2-10 minutes, witha viscosity sufficiently high to allow the material to remain onaneurytic tissue or within an aneurysm for 1-1000; 2-100; 2-50; 2-25; or2-10 minutes, or with a viscosity sufficiently high to allow thematerial to remain on aneurytic tissue or within an aneurysm long enoughfor the material to gel, harden, or solidify.

Component II

The base material may comprise any of the Component I materialsdescribed above, or the base material may comprise any combination ofthe Component I materials described above. Moreover, the base materialmay contain any other material that does not interfere with the functionor operation of the base material so much that one of ordinary skill inthe art would reject adding that other material. Some of those othermaterials are described below under the Component II and Component IIIheadings.

Another optional component is a contrast medium for reasons describedabove or for other reasons. Useful contrast media include materialscomprising metrizamide, iodecimol, ioglucol, ioglucamide, ioglunide,iogulamide, iomeprol, iopentol, iopromide, iosarcol, iosimide, iotasul,ioxilan, iohexyl, ioversol, iopamidol, iotrolan, ioxaglate, iodixanol,iothalamate, ioxithalamate, iodamide, metrizoate, copper-zinc ferrite,nickel-zinc ferrite, manganese-zinc ferrite, zinc ferrite, magnesiumferrite, α-ferric oxide, ferrosoferric oxide, diatrizoate, bariumsulfate, diatrizoic acid, metrizoic acid, iotalamic acid, ioxitalamicacid, ioglicic acid, acetrizoic acid, iocarmic acid, methiodal, diodone,ioxaglic acid, iobitridol, iodoxamic acid, iotroxic acid, ioglycamicacid, adipiodone, iobenzamic acid, iopanoic acid, iocetamic acid, sodiumiopodate, tyropanoic acid, calcium iopodate, ethyl esters of iodizedfatty acids, iopydol, propyliodone, iofendylate, or lipiodol.

For purposes of this disclosure, a sufficient amount of a materialcomprising contrast media means that the material comprises enoughcontrast media to make the mixture medically imageable. For purposes ofthis disclosure, medically imageable means that the material is visibleenough when imaged with a radiological device that the person treatingthe patient is able to detect that the mixture is entering thevasculature and to what extent the mixture is entering the vasculaturein substantially real time. For purposes of this disclosure, aradiological device is any device capable of viewing inside a patient'sbody non-invasively, irrespective of whether or not the device employselectromagnetic radiation as part of the viewing process.

Other optional components in the filling material are drugs such aspro-healing drugs or growth factors. In some embodiments, an optionaldrug component is any pro-healing drug or growth factor or anycombination of pro-healing drugs or growth factors.

As used herein, “pro-healing” refers to a moiety that aids in thehealing process at the aneurysm or within the aneurysm. Pro-healingdrugs are useful as drugs and are optionally added to the fillingmaterial. In some embodiments, pro-healing drugs are materials thatpromote the controlled proliferation of muscle cells with a normal andphysiologically benign composition, useful pro-healing drugs includeenzymes, anti-inflammatory agents, antivirals, anticancer drugs,anticoagulant agents, free radical scavengers, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,antibiotics, estradiol, VEGF, an EPC antibody, biorest, nitric oxidedonors, super oxide dismutases, endothelial progenitor cells, superoxide dismutases mimics, nitric oxide,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),dexamethasone, clobetasol, aspirin, pro-drugs of these drugs, co-drugsof these drugs. Any compatible combination of pro-healing drug is alsosuitable for use in this invention.

The polypeptide Arg-Gly-Asp (RGD) has been demonstrated to be abioactive factor for human endothelial cell attachment and therefore isexpected to exhibit prohealing characteristics. In addition to RGDitself, cyclic RGD (cRGD) and RGD mimetics and small molecules capableof binding as does RGD to other adhesion receptors are within the scopeof optional filling material components. RGD mimetics can be prepared bymodification of RGD or cRGD. Peptide synthesis, including the synthesisof peptide mimetics, is well documented and can be readily achievedusing, for example, combinatorial chemistry. Some examples of cRGD orRGD mimetics include V3 antagonists such as IIb/IIIb antagonists, oneexample of which is Abciximax; XJ 735; anti-3-integrin antibody F11;cRGD; and other sequences such as laminin-derived SIKVAV;laminin-derived YIGSR; KQAGDV; and VAPG.

Useful drugs also include any substance or combination of substancescapable of exerting a therapeutic or prophylactic effect in the practiceof the present invention as well as having positive pharmacologicaleffects on the expression of the extracellular matrix. The activeingredient can also enhance wound healing in a vascular site or improvethe structural and elastic properties of the vascular site.

Growth factors are also useful drugs in this invention. Growth factorsinclude any one or any combination of vasoendothelial growth factor,fibroblast growth factor, hypoxia inducing factor, monocytechemoattractant protein, lipid factors, vascular endothelial growthfactors, fibroblast growth factors, nicotine, platelet derived growthfactor, insulin-like growth factor 1, transforming growth factor,hepatocyte growth factor, estrogens, follistatin, proliferin,prostaglandin E1, prostaglandin E2, tumor necrosis factor,interleukin-8, hematopoietic growth factors, erythropoietin,granulocyte-colony stimulating factors, and platelet-derived endothelialgrowth factor.

Angiogenic substances are growth factors and may be any one or anycombination of the following substances, and hormones and genes thatencode any one of the following substances: vascular endothelial growthfactor, fibroblast growth factors, monocyte chemoattractant proteins,transforming growth factor beta, transforming growth factor alpha, lipidfactors, hypoxia-inducible factor 1-alpha, PR39, nicotine, insulin-likegrowth factors, placental growth factor, hepatocyte growth factor,estrogen, follistatin, proliferin, cytokines, tumor necrosis factor,erythropoietin, granulocyte colony-stimulating factor, granulocytemacrophage colony-stimulating factor, and angiogenin.

Also, endogenous compounds may be added to these compounds as drugs, seebelow.

Anti-inflammatory agents may be added to the filling material mixture.Suitable anti-inflammatory agents include, without limitation, steroidalanti-inflammatory agents, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory agentsinclude clobetasol, alclofenac, alclometasone dipropionate, algestoneacetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium,amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone,balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride,bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone,cliprofen, clobetasol propionate, clobetasone butyrate, clopirac,cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort,desonide, desoximetasone, dexamethasone dipropionate, diclofenacpotassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, morniflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof. The anti-inflammatory agent may also be a biological inhibitorof pro-inflammatory signaling molecules including antibodies to suchbiological inflammatory signaling molecules.

Depending on their source, the components may contain trace amounts ofextraneous, but supposedly benign materials. Thus, the compositions ofthis invention may comprise one or more of these trace materials. Forexample, an avian-sourced glycosaminoglycan or mucopolysaccharide maycontain trace amounts of avian protein, which in turn leads to inventiveembodiments that may comprise avian protein.

In some embodiments, the filling materials or components of the fillingmaterials are prepared to be hydrogels.

For purposes of this document, filling materials assembled or producedoutside of the patient are referred to as stage I materials. After astage I material is delivered to the aneurysm, the patient's body beginsto break the material down. Moreover, during this time, blood cells andproteins migrate into the stage I material creating a new materialwithin the aneurysm—called a stage II material. The stage II material,formed in situ, is suitable for filling aneurysms. Thus, a stage IImaterial may comprise any of the components of the stage I material, maycomprise blood cells or blood proteins, may comprise glycosaminoglycanor mucopolysaccharide decomposition products, may comprise blood cell orblood protein decomposition products, may comprise other endogenousmaterials or may comprise, for those embodiments employing some type ofcoil, materials arising from the coil's decomposition.

Endogenous materials include those materials created by the patient'sbody that one of ordinary skill in the art would expect the patient'sbody to create or deposit near the aneurysm treatment site.Specifically, endogenous compounds include among other compounds,extracellular matrix. The extracellular matrix is the extracellular partof animal tissue that usually provides structural support to the animalcells in addition to performing various other important functions. Theextracellular matrix is the defining feature of connective tissue inanimals. Extracellular matrix includes the interstitial matrix and thebasement membrane. Interstitial matrix is present between various animalcells (i.e., in the intercellular spaces). Gels of polysaccharides andfibrous proteins fill the interstitial space and act as a compressionbuffer against the stress placed on the matrix. The extracellular matrixis composed of an interlocking mesh of fibrous proteins andglycosaminoglycans (GAGs). GAGs are carbohydrate polymers and areusually attached to extracellular matrix proteins to form proteoglycans.Heparan sulfate is a linear polysaccharide found in all animal tissues.Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chainof alternating sugars. Keratan sulfate, also called keratosulfate, isany of several sulfated glycosaminoglycans that have been foundespecially in the cornea, cartilage, and bone. Collagen is a group ofnaturally occurring proteins. In nature, it is found exclusively inanimals, especially in the flesh and connective tissues of mammals. Itis the main component of connective tissue, and is the most abundantprotein in mammals, making up about 25% to 35% of the whole-body proteincontent. Collagen, in the form of elongated fibrils, is mostly found infibrous tissues such as tendon, ligament and skin, and is also abundantin cornea, cartilage, bone, blood vessels, the gut, and intervertebraldisc. Elastin is a protein in connective tissue that is elastic andallows many tissues in the body to resume their shape after stretchingor contracting. Elastin helps skin to return to its original positionwhen it is poked or pinched. Fibronectins are proteins that connectcells with collagen fibers in the extracellular matrix. Laminins aremajor proteins in the basal lamina, a protein network foundation formost cells and organs. Generally see Extracellular Matrix article onWikipedia.org.

The difference between the extracellular matrix materials described hereas endogenous compounds and those described above as Component Iconstituents is that the endogenous compounds are prepared by thepatient's body and become involved with the aneurysm because of thetreatment of the aneurysm. The ones described above, although of similaror perhaps nearly identical structure are typically producedsynthetically or by another organism. But this need not be the case.

In some embodiments, the stage I material decomposes and eventuallysubstantially completely decomposes. In some of these embodiments, thestage I material substantially completely decomposes after 7-90 days.

Delivery

The practitioner can deliver the filling material percutaneously using acatheter system, a balloon catheter system, or a needle catheter system.Alternatively, the practitioner can deliver the material directly to theaneurysm by hypodermic needle injection or by some surgical techniquessuch as open surgery or laparoscopic surgery.

Some embodiments comprise a treatment method wherein an aneurysm isvisualized such as by fluoroscopy. A catheter or other delivery devicesis inserted into the patient percutaneously and tracked along thevasculature until the delivery device is positioned near the aneurysm.One way of doing this is tracking a catheter over a guidewire. Once thedelivery device is correctly positioned near the aneurysm, a fillingmaterial is delivered to the aneurysm. Some embodiments of the fillingmaterial comprise a glycosaminoglycan and, optionally, a contrast media,a physiological buffer or both. In these or other embodiments, thefilling material comprises a glycosaminoglycan selected from hyaluronicacid, sodium hyaluronate, chondroitin sulfate, dermatan sulfate, keratansulfate, or heparin sulfate; and optionally a contrast media, aphysiological buffer, or both. In these or other embodiments, thecontrast media is selected from material comprising metrizamide,iodecimol, ioglucol, ioglucamide, ioglunide, iogulamide, iomeprol,iopentol, iopromide, iosarcol, iosimide, iotasul, ioxilan, iohexyl,ioversol, iopamidol, iotrolan, ioxaglate, iodixanol, iothalamate,ioxithalamate, iodamide, metrizoate, copper-zinc ferrite, nickel-zincferrite, manganese-zinc ferrite, zinc ferrite, magnesium ferrite,α-ferric oxide, ferrosoferric oxide, diatrizoate, barium sulfate,diatrizoic acid, metrizoic acid, iotalamic acid, ioxitalamic acid,ioglicic acid, acetrizoic acid, iocarmic acid, methiodal, diodone,ioxaglic acid, iobitridol, iodoxamic acid, iotroxic acid, ioglycamicacid, adipiodone, iobenzamic acid, iopanoic acid, iocetamic acid, sodiumiopodate, tyropanoic acid, calcium iopodate, ethyl esters of iodizedfatty acids, iopydol, propyliodone, iofendylate, or lipiodol.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from theembodiments of this invention in its broader aspects and, therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true spirit and scope of theembodiments of this invention. Additionally, various embodiments havebeen described above. For convenience's sake, combinations of aspectscomposing invention embodiments have been listed in such a way that oneof ordinary skill in the art may read them exclusive of each other whenthey are not necessarily intended to be exclusive. But a recitation ofan aspect for one embodiment is meant to disclose its use in allembodiments in which that aspect can be incorporated without undueexperimentation. In like manner, a recitation of an aspect as composingpart of an embodiment is a tacit recognition that a supplementaryembodiment exists that specifically excludes that aspect. All patents,test procedures, and other documents cited in this specification arefully incorporated by reference to the extent that this material isconsistent with this specification and for all jurisdictions in whichsuch incorporation is permitted.

Moreover, some embodiments recite ranges. When this is done, it is meantto disclose the ranges as a range, and to disclose each and every pointwithin the range, including end points. For those embodiments thatdisclose a specific value or condition for an aspect, supplementaryembodiments exist that are otherwise identical, but that specificallyexclude the value or the conditions for the aspect.

Finally, headings are for the convenience of the reader and do not alterthe meaning or content of the disclosure or the scope of the claims.

What is claimed is:
 1. A composition comprising a mixture of anon-particulate, flowable, non-fibrotic glycosaminoglycan ormucopolysaccharide, and a sufficient amount of a material comprisingcontrast media such that the mixture is medically imageable.
 2. Thecomposition of claim 1 further comprising a physiological buffer.
 3. Thecomposition of claim 2 further comprising avian protein.
 4. Thecomposition of claim 2 wherein the glycosaminoglycan ormucopolysaccharide is selected from hyaluronic acid, sodium hyaluronate,chondroitin sulfate, dermatan sulfate, keratan sulfate, or heparinsulfate.
 5. The composition of claim 2 further comprising blood proteincomponents, blood protein decomposition products, blood cells, bloodcell decomposition products, other endogenous compounds, aneurytictissue components, aneurytic tissue decomposition products, or coildecomposition products.
 6. The composition of claim 5 wherein theglycosaminoglycan or mucopolysaccharide has a hydrogel nature, has ahigh viscosity, and is non-thrombogenic.
 7. The composition of claim 1wherein the glycosaminoglycan or mucopolysaccharide is selected fromhyaluronic acid, sodium hyaluronate, chondroitin sulfate, dermatansulfate, keratan sulfate, or heparin sulfate.
 8. The composition ofclaim 7 wherein the contrast media is selected from metrizamide,iodecimol, ioglucol, ioglucamide, ioglunide, iogulamide, iomeprol,iopentol, iopromide, iosarcol, iosimide, iotasul, ioxilan, iohexyl,ioversol, iopamidol, iotrolan, ioxaglate, iodixanol, iothalamate,ioxithalamate, iodamide, metrizoate, copper-zinc ferrite, nickel-zincferrite, manganese-zinc ferrite, zinc ferrite, magnesium ferrite,α-ferric oxide, ferrosoferric oxide, diatrizoate, barium sulfate,diatrizoic acid, metrizoic acid, iotalamic acid, ioxitalamic acid,ioglicic acid, acetrizoic acid, iocarmic acid, methiodal, diodone,ioxaglic acid, iobitridol, iodoxamic acid, iotroxic acid, ioglycamicacid, adipiodone, iobenzamic acid, iopanoic acid, iocetamic acid, sodiumiopodate, tyropanoic acid, calcium iopodate, ethyl esters of iodizedfatty acids, iopydol, propyliodone, iofendylate, or lipiodol.
 9. Thecomposition of claim 8 wherein the molecular ratio of glycosaminoglycanor mucopolysaccharide to contrast media ranges from 1.2:1 to1,000,000:1.
 10. A composition comprising a mixture of anon-particulate, flowable, non-fibrotic glycosaminoglycan and asufficient amount of a material comprising contrast media such that themixture is medically imageable and wherein the contrast media isselected from metrizamide, iodecimol, ioglucol, ioglucamide, ioglunide,iogulamide, iomeprol, iopentol, iopromide, iosarcol, iosimide, iotasul,ioxilan, iohexyl, ioversol, iopamidol, iotrolan, ioxaglate, iodixanol,iothalamate, ioxithalamate, iodamide, metrizoate, copper-zinc ferrite,nickel-zinc ferrite, manganese-zinc ferrite, zinc ferrite, magnesiumferrite, α-ferric oxide, ferrosoferric oxide, diatrizoate, bariumsulfate, diatrizoic acid, metrizoic acid, iotalamic acid, ioxitalamicacid, ioglicic acid, acetrizoic acid, iocarmic acid, methiodal, diodone,ioxaglic acid, iobitridol, iodoxamic acid, iotroxic acid, ioglycamicacid, adipiodone, iobenzamic acid, iopanoic acid, iocetamic acid, sodiumiopodate, tyropanoic acid, calcium iopodate, ethyl esters of iodizedfatty acids, iopydol, propyliodone, iofendylate, or lipiodol.
 11. Thecomposition of claim 10 wherein the glycosaminoglycan is hyaluronicacid.
 12. The composition of claim 11 wherein the composition is adaptedto migrate out of the aneurysm or break down within the aneurysm and bereplaced with endogenous compounds over 7-90 days.
 13. The compositionof claim 12 wherein the hyaluronic acid has a hydrogel nature, has ahigh viscosity, and is non-thrombogenic.
 14. The composition of claim 13wherein the molecular ratio of glycosaminoglycan to contrast mediaranges from 1.2:1 to 1,000,000:1.
 15. The composition of claim 10wherein the composition is adapted to migrate out of the aneurysm orbreak down within the aneurysm and be replaced with endogenous compoundsover 7-90 days.
 16. The composition of claim 15 wherein the molecularratio of glycosaminoglycan to contrast media ranges from 1.2:1 to1,000,000:1.
 17. A method comprising supplying a mixture of anon-particulate, flowable, non-fibrotic glycosaminoglycan ormucopolysaccharide, and a sufficient amount of a material comprisingcontrast media such that the mixture is medically imageable, anddelivering the mixture to an aneurytic site in mammalian vasculature.18. The method of claim 17 wherein the glycosaminoglycan ormucopolysaccharide is selected from hyaluronic acid, sodium hyaluronate,chondroitin sulfate, dermatan sulfate, keratan sulfate, or heparinsulfate.
 19. The method of claim 17 wherein the contrast media isselected from metrizamide, iodecimol, ioglucol, ioglucamide, ioglunide,iogulamide, iomeprol, iopentol, iopromide, iosarcol, iosimide, iotasul,ioxilan, iohexyl, ioversol, iopamidol, iotrolan, ioxaglate, iodixanol,iothalamate, ioxithalamate, iodamide, metrizoate, copper-zinc ferrite,nickel-zinc ferrite, manganese-zinc ferrite, zinc ferrite, magnesiumferrite, α-ferric oxide, ferrosoferric oxide, diatrizoate, bariumsulfate, diatrizoic acid, metrizoic acid, iotalamic acid, ioxitalamicacid, ioglicic acid, acetrizoic acid, iocarmic acid, methiodal, diodone,ioxaglic acid, iobitridol, iodoxamic acid, iotroxic acid, ioglycamicacid, adipiodone, iobenzamic acid, iopanoic acid, iocetamic acid, sodiumiopodate, tyropanoic acid, calcium iopodate, ethyl esters of iodizedfatty acids, iopydol, propyliodone, iofendylate, or lipiodol; and theglycosaminoglycan or mucopolysaccharide is selected from hyaluronicacid, sodium hyaluronate, chondroitin sulfate, dermatan sulfate, keratansulfate, or heparin sulfate.
 20. The method of claim 19 whereindelivering the mixture comprises inserting a needle into the aneurysm ordelivering a catheter or needle catheter delivery system device to theaneurytic site and depositing the composition into the aneurysm.
 21. Themethod of claim 20 further comprising delivering a coil to the aneurysmbefore, during, or after delivering the mixture.
 22. The method of claim18 wherein delivering the composition comprises inserting a needle intothe aneurysm or delivering a catheter or needle catheter delivery systemdevice to the aneurytic site and depositing the composition into theaneurysm.
 23. The method of claim 22 further comprising delivering acoil to the aneurysm before, during, or after delivering the mixture.24. The method of claim 19 wherein delivering the mixture comprisesinserting a needle into the aneurysm or delivering a catheter or needlecatheter delivery system device to the aneurytic site and depositing thecomposition into the aneurysm.
 25. The method of claim 24 furthercomprising delivering a coil to the aneurysm before, during, or afterdelivering the mixture.